Mathematical Modelling of DNA Replication Reveals a Trade-off between Coherence of Origin Activation and Robustness against Rereplication
Figure 6
Mechanism of multisite protein phosphorylation.
(A) Mixed random-sequential phosphorylation of Sld2: six Ser/Thr residues are phosphorylated randomly, giving rise to a large number of possible phosphorylation pathways (states 0: unphosphorylated and 1: phosphorylated). Together, these phosphorylations cause a conformational change that allows phosphorylation of the essential Thr84 (state indicated in red), the docking site for Dpb11. (B) In agreement with experimental data [38], the model gives rise to hyperbolic time course for each of the initial six Ser/Thr residues (black curve), while Thr84 (red curve) is phosphorylated with a time delay. To mirror the in-vitro assay conditions, the model simulation was performed without phosphatase activity. (C) The mean time for complete phosphorylation rises with the number of phosphorylation sites (the increase is less than linear because of the random phosphorylation mechanism), while (D) the temporal coherence of phosphorylation increases (decreasing Δ/τ). (E) The robustly high temporal coherence of protein activation by multisite phosphorylation (low Δ/τ) contrasts with the strong dependence of single-site phosphorylation on the activation time of the input kinase, σ (see upper panel).